The main function of the nose is to warm, filter and moisturize incoming air. Nasal passages are lined with an epithelial cell layer called nasal mucosa, composed of different cell types. Some cells secrete a gel-like substance called mucus, composed mainly of water, and very small amount is of mucin and inorganic salts. The mucus layer functions as a trap for all noxious substances entering the nose such as dust, bacteria, and viruses.
Mucus is cleared from the nose by millions of cilia on top of the ciliated columnar cells in the nasal mucosa. These cilia “sweep” mucus and trapped material through the nasal passages in the direction of the back of the throat where it is swallowed. This line of defense, protecting the human body against all noxious material (bacteria, allergens, and viruses) entering the nose, is called nasal mucociliary clearance. Impairment of the nasal mucociliary clearance results in diseases of the upper airways. Therefore, it may be advantageous to stimulate nasal mucociliary clearance by a nasal medication and activate the natural defense mechanism of the nose to prevent viral, bacterial or allergic diseases. Such a nasal medication may clean the nasal passages and offer relief and defense against infectious and allergic diseases.
Normal nasal mucociliary transit time (also called Mucus Transit Time, MTT) in humans has been reported to be about 15-20 min. Transit times of more than 30 min are considered to be abnormal, and are an indication of impaired mucociliary clearance. The average rate of nasal clearance is about 8 mm/min, ranging from less than 1 to more than 20 mm/min. It has been demonstrated with nasal sprays containing a radiolabeled compound, that clearance takes place in two phases. The first phase lasts about 15-20 min, in which the major part of the administered dose is cleared from the ciliated nasal respiratory mucosa. The second clearance phase is slower, and removes the part of the nasal medication that is deposited on the non-ciliated vestibule and anterior septal area in the nose. The first phase dominates the clearance of allergens, bacteria and viruses from the major respiratory passages in the nose.
A simple and inexpensive method for estimating the mucociliary clearance and the MTT in vivo is by using dyes as a marker. Drops or particles coloured by a strong dye are placed into the anterior part of the nasal cavity. The time for the dye to appear in the pharyngeal cavity is measured by monitoring its appearance in the pharyngeal cavity. Regular inspection is needed. Another method uses a sweet-tasting particle, usually saccharin, deposited in the anterior part of the nasal cavity. The time between deposition and sensation of a sweet taste is taken as the MTT. A disadvantage of the saccharin test is that some subjects have a high taste threshold or do not taste the saccharin properly. Also, it is not possible to do several saccharin tests in a short period of time, because the taste of saccharin takes hours to disappear completely. To compensate for the disadvantages of both methods, a combination of a dye and saccharin may be used.
Most nasal products on the market are used to treat nasal congestion (stuffy nose). The nose gets congested (stuffy) when the nasal epithelial tissue and the blood vessels are inflamed and swollen. Nasal congestion can interfere with the ears, hearing, speech development and sleep. A stuffy nose is usually caused by a virus or bacteria. Causes include a common cold, influenza, sinus infection, also allergies such as hay fever, nasal polyps and vasomotor rhinitis. Nasal decongestants are widely used. However, a so-called rebound nasal congestion occurs in patients taking nasal decongestants, like oxymetazoline, more than twice daily and for more than 3-5 consecutive days. This indicates that there is a strong medical need to treat nasal congestion and nasal infections with a medication that is free from decongestants and a medication that can be used for a longer period than 3-5 days, and preferably longer than 5 days.
Also, it has been proven that nasal saline solutions, widely used by millions of patients, often impair the ciliary activity, and consequently reduce the nasal mucociliary clearance and increase nasal MTT. Also many nasal products on the market contain preservatives which are not only rather toxic but also responsible for a serious reduction of the ciliary activity.
Accordingly, a medical need exists for nasal medications including sprays and drops, preferably without preservatives, providing aqueous nasal compositions comprising one or more agents and excipients in an amount sufficient to (1) stimulate ciliary movement and nasal mucociliary clearance and (2) decrease the nasal mucus transit time (3) remove noxious materials as soon as possible to prevent viral, bacterial and allergenic diseases in the upper airways. Also there is a need for a nasal medication that (4) can be used for a longer period of time (longer than 3-5 days) to treat or prevent nasal congestion.
During investigations carried out by the applicant on ciliated cells exposed to sodium chloride solution (NaCl 0.9 percent w/v in water, also called saline), the ciliary beat frequency (CBF) was found to increase after the addition of small amounts of potassium chloride, calcium chloride and water, optionally together with small amounts of sodium bicarbonate and glucose. The CBF of ciliated human nasal and chicken tracheal tissue was also surprisingly found to remain constant over many hours in isotonic solutions containing a combination of sodium, potassium and calcium chloride salts; while in solutions containing only NaCl (0.9 percent) the CBF decreased to 50-70 percent of the initial value within 1-2 hours. This indicates that the presence of sodium, potassium and calcium ions in specific concentrations is necessary for stimulation/activation of the ciliary movement and optimal functioning of the mucociliary clearance in the nose. The presence of these salts is especially required when nasal compositions are used on a daily basis for weeks. Supportive evidence for the specific function of these ions can be found in the literature, for instance “Ca-ions in mucociliary tissue of higher organisms are essential for ciliary beating, with a rise in intracellular Ca-ions correlating with a rise in ciliary beat frequency” (Braiman et al, Purinergic stimulation of ciliary activity, Drug Development Research 2000; 50:550-554).
Further investigations (see under Experimental Section) on chicken embryo ciliated tissue and on human nasal ciliated cell cultures surprisingly demonstrated that xanthine derivates in small amounts increased the CBF for a long time. Compositions, called Ciliactive®, were prepared by adding a xanthine derivative such as caffeine and/or theobromine (up to 0.5 percent w/v) to aqueous isotonic solutions, comprising sodium chloride and small amounts of potassium chloride and calcium chloride. Cilia experiments using human ciliated cell cultures with these Ciliactive® solutions showed a very significant increase in ciliary beat frequency (CBF) in comparison with the CBF measured after exposure of the ciliated cells to caffeine-free saline or culture medium solutions. The caffeine in the Ciliactive® solution thus acts synergistically with the salt component (sodium-potassium-calcium salts) to achieve a strong and long-lasting effect on the CBF. Ciliactive® may be used daily for weeks or months without the depletion of important ions in the nasal mucosa, and is a highly effective longterm medication for the treatment or prevention of nasal congestion or nasal allergic or infectious diseases, or for nasal cleansing.
Compared with the effect of saline, the increase of CBF under the influence of Ciliactive® was very statistically significant after 5 hours, also after 24 hours, and also after 48 hours, with p-values of respectively 0.003, 0.001 and 0.005. As a result, it may be concluded that solutions containing caffeine and also sodium chloride, potassium chloride and calcium chloride stimulate mucociliary clearance in the human nose, because ciliary movement is the driving force of mucociliary clearance in the human nose.
Certain known nasal products contain caffeine. U.S. Pat. No. 5,169,849 (Kiechel et al.) discloses a liquid nasal pharmaceutical composition which contains the antimigraine drug dihydroergotamine which is capable of depressing ciliary function and an effective amount of a xanthine, for instance caffeine, which is capable of increasing the ciliary function again over a period of 20 minutes after application of the antimigraine drug and the xanthine in a nasal spray. The purposes of the xanthine is to counteract the depressive effect of the antimigraine drug on CBF following administration. The weight ratio of the dihydroergotamine to the xanthine is from 0.1:1 to 10:1.
U.S. Pat. No. 5,508,282 teaches a nasal composition and method for treating acute or chronic rhinosinusitis containing caffeine. The active substance caffeine is “employed as a topical vasoconstrictor” (column 3 line 57-58). The preferred amount of caffeine is 1.7 percent (17 mg/ml) and the contemplated range is 5-100 mg/ml (column 3, line 63-64). According to “the most preferred embodiment of the present disclosure” the formulation contains also benzoic acid or sodium benzoate 17 mg/ml” (column 4, lines 5-35), in a similar amount as caffeine. However, such a combination as proposed by U.S. Pat. No. 5,508,282 is not advantageous from a scientific point of view. The Pharmaceutical Codex, 12th edition teaches that sodium benzoate (and/or benzoic acid) is a solubilizer for caffeine, because it builds a complex with caffeine. Caffeine itself is not soluble in water at room temperature in a concentration above 16 mg/ml (The Pharmaceutical Codex, W. Lund, Editor, 12th edition, The Pharmaceutical Press, London 1994, pp 771-772). Also, sodium benzoate is a preservative. From the literature it is known that preservatives inhibit nasal ciliary movement and therefore the use of sodium benzoate may be harmful (e.g. Mallants R et al, Effect of preservatives on ciliary beat frequency in human nasal epithelial cell culture; single and multiple exposure, Int. J. Pharmaceutics 2007; 338:64-69). Further, the FDA only considers sodium benzoate as a safe excipient in food when the concentration is limited to 0.1 percent by weight and in U.S. Pat. No. 5,508,282 the preferred concentration of sodium benzoate is higher (source:www.accessdata.fda.gov/sodium benzoate 184.1733)
One of the methylxanthines, theophylline, is a drug mainly used as an asthma medicine and prescribed as tablet or oral syrup to facilitate mucociliary clearance. G. Mathe et al. (Biomed. Pharmacotherapy 1988; 42:489-492) teach that acid air pollution may play a part in the mucus cilia transport syndrome, as the respiratory mucus does not tolerate an acid pH. Their advice is to apply alkaline aerosols and also to use theophyllin because it “activates cilia mobility, usually increase mucus fluidity and facilitate its clearance from the sinuses”.
US2011/086114 describes nasal compositions for moisturizing nasal passages and for stimulating mucous transport by increasing ciliary beat frequency, comprising Ascorbic acid (Vitamin C), but not caffeine or theobromine.
WO98/42322 teaches that theobromine can be used as an antitussive agent because it stimulates mucociliary clearance, and discloses for instance a solution of theobromine 25 percent (w/w) in an oral syrup with 30 percent (w/w) saccharose in water to alleviate irritable cough.
Several patent applications disclose compositions for administration on the mucous membranes comprising amounts of a xanthine derivative. For instance, caffeine to improve the sense of a refrigerant (e.g. menthol) on a mucous membrane (JP2001 302518) or caffeine, theophylline or the like to stabilize an azulene derivative in an aqueous composition (JP2003 128537). The stability of vitamin E is improved by including a xanthine (caffeine and others) in the compositions for mucous membranes (JP2003 128552), and similarly also the stability of chlorpheniramine and its salts is improved when compounded with a xanthine like caffeine (JP2003 128549).
Also others have proposed caffeine in a nasal medication. U.S. Pat. No. 4,778,810 teaches the use of a nasal medication wherein caffeine is used as the only therapeutically active ingredient, in an extreme high dose, and used for its central stimulating effect. The concentration described is 25 mg/ml to 2000 mg/ml. Also on the internet a caffeine energy nasal spray (called “Turbo snort”) is promoted containing about 1 percent caffeine (10 mg/ml of caffeine), providing for instance 4 sprays of in total 0.365 ml, containing about 4 mg of caffeine. Suggested use is to increase energy, alertness and performance. The solution contains not only caffeine but also creatine, taurine, glutamine, ascorbic acid, water, and glycerin (www.turbosnort.com).
Several medications comprising inorganic salt compositions have been disclosed to treat rhinitis and other nasal symptoms. U.S. Pat. No. 7,541,052 discloses a method of treating a patient suffering from inflammation and/or irritation of the nasal passageways which comprises nasally administering an aqueous hypertonic composition consisting essentially of about 1 to 10 percent by weight of salts consisting essentially of: A) 1) about 45 to 60 percent by weight of magnesium chloride; 2) about 29 to 40 percent by weight of potassium chloride, and 3) about 0.4 to 5 percent by weight of salts selected from the group consisting of magnesium bromide, calcium chloride, calcium bromide, sodium bromide and magnesium sulfate, and B) the remainder being water, whereby mucus secretion is induced and the irritation or inflammation is reduced.
WO01/00218 discloses a similar composition in water, consisting essentially of about 0.5 to 5 percent by weight of a Dead Sea salt and mineral composition, including about 31-35 percent magnesium halide, 24-26 percent potassium halide, 4-8 percent sodium halide, 0.4-0.6 percent calcium halide, the halide being 0.3-0.6 percent bromide and about 99.4-99.7 percent chloride. Both compositions of salts of U.S. Pat. No. 7,541,052 and WOo 1/00218 differ largely from the composition of human plasma and human airway (nose) surface fluids. According to Joris et al, the composition of airway surface fluid and plasma levels in human volunteers is Na (mM) 82 and 139, K (mM) 29 and 4, and Ca (mM) 4 and 2.4 (Joris et al, Elemental composition of human airway surface fluid in healthy and diseases airways, Am. Rev. Respir. Dis. 1993; 148:1633-1637). The extremely large amounts of magnesium salts, the presence of bromides, and the overall composition of U.S. Pat. No. 7,541,052 and WOoi/00218 differ completely from the present disclosure composition. The composition of the present disclosure composition contains sodium, potassium and calcium salts (as chloride) in physiologically acceptable amounts, and in a concentration largely comparable to the concentration present in human plasma and human airway surface fluid.
The applicants have surprisingly found that nasal compositions containing low-concentrations of caffeine and/or theobromine advantageously work as a ciliary stimulant when administered in an aqueous composition at a pH of about 6-8, containing also—sodium, calcium and potassium salts, preferably selected from NaCl, KCl, CaCL, and optionally also containing NaHCO3, glucose, various buffers and/or small amounts of other inorganic salts and/or other salts such as acetates, lactates, sulphates and phosphates. By using these low concentrations of caffeine any potential central stimulating effect of caffeine is avoided, because the total amount of caffeine administered is negligible and serves only to stimulate ciliary activity in the nose. Also, solubility problems with caffeine in aqueous compositions (requiring the use of solubilizers and/or complex formation by sodium benzoate) are avoided when such low concentrations of caffeine are used.